Phase II SBIR: WHI-07: A Novel Dual-Function Microbicide

II 期 SBIR：WHI-07：一种新型双功能杀菌剂

基本信息

批准号：
6952352
负责人：
OSMOND J D'CRUZ
金额：
$ 37.87万
依托单位：
PARADIGM PHARMACEUTICALS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-08-01 至 2007-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The current pandemic of sexually transmitted HIV/AIDS has created an urgent need for a new type of microbicide: one that is both a spermicide and a virucide. The goal of the proposed Phase II work is to further develop WHI-07, a novel 5-bromo 6-methoxy aryl phosphoramidate derivative of 3'-azido-3'-deoxythymidine (zidovudine, ZDV/AZT) as a dual-function anti-HlV microbicide. WHI-07 was rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions. WHI-07 was formulated via a nontoxic gel-microemulsion for intravaginal use as a potential candidate anti-HIV spermicide. The in vivo efficacy as well as safety studies of WHI-07 have included: (i) vaginal as well as rectal microbicide efficacy studies in the feline immunodeficiency vires (FIV)/domestic cat model for AIDS; (ii) in vivo retention of anti-HIV activity in the nonhuman primate; (iii) vaginal contraceptive efficacy studies in rabbits; (iv) single- and/or multiple-dose toxicity studies in mice, rabbits, cats as well as monkey; (v) mucosal, reproductive, and developmental toxicity studies in mice and rabbits; (vi) cytotoxicity, mutagenicity, and genotoxicy tests using human and yeast cells; and (vii) long-term carcinogenicity studies in mice. Under Phase I proposal we tested: (i) the ability of WHI-07 to prevent transvaginal as well as transrectal transmission of FIV in domestic cats as a model for sexual transmission of HIV; and (ii) determined the lack of developmental toxicity of WHI-07 in the rabbit model. Our discovery that WHI-07 either alone or in combination with a bis(cyclopentadienyl) vanadium(IV) complex, vanadocene dithiocarbamate (VDDTC), effectively protected domestic cats from systemic FIV infection via genital exposure to mucosally transmissible FIV-infected feline T cells has clinical potential for the development of a dual-function anti-HIV microbicide for sexually active women. Under Phase II funding, we propose to test the in vivo antiretroviral and contraceptive efficacies as well as safety studies of WHI-07 plus VDDTC gel-microemulsion to further explore the utility of WHI-07 either alone and in combination with VDDTC as a vaginal spermicidal anti-HIV microbicide in the clinical setting. We hypothesize that the combination of these two active agents with different mechanisms of action will potentially improve efficacy and duration of dual-protection when compared to WHI-07 alone while maintaining an adequate safety profile. The goals of Phase II study are (i) to examine the optimum microbicide activity of WHI-07 plus VDDTC gel-microemulsion versus WHI-07 alone to prevent systemic FIV infection of domestic cats from transvaginal and transrectal challenge with FIV-infected cells; (ii) to evaluate the in vivo contraceptive efficacy of WHI-07 plus VDDTC gel-microemulsion in rabbits; (iii) to assess the mucosal safety and developmental toxicity of WHI-07 plus VDDTC gel-microemulsion in rabbits; and (iv) to assess the stability WHI-07 plus VDDTC in-gel-microemulsion. The proposed Phase II work will complement and enhance the discovery and preclinical development of safe and effective dual-function microbicides at Paradigm Pharmaceuticals that may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing effective fertility control for women.

描述（由申请人提供）：当前性传播艾滋病毒/艾滋病的流行迫切需要一种新型杀微生物剂：一种既是杀精剂又是杀病毒剂的杀微生物剂。拟议的第二阶段工作的目标是进一步开发 WHI-07，一种新型 3'-叠氮基-3'-脱氧胸苷（齐多夫定，ZDV/AZT）的 5-溴 6-甲氧基芳基氨基磷酸酯衍生物，作为双功能抗-HIV杀微生物剂。 WHI-07 经过合理设计，可绕过生殖道分泌物中 ZDV 激活的胸苷激酶依赖性。 WHI-07 通过无毒凝胶微乳液配制而成，可作为潜在的候选抗 HIV 杀精剂在阴道内使用。 WHI-07 的体内功效和安全性研究包括：(i) 在猫免疫缺陷病毒 (FIV)/艾滋病家猫模型中进行阴道和直肠杀微生物剂功效研究； (ii) 在非人类灵长类动物体内保留抗 HIV 活性； (iii) 兔子阴道避孕效果研究； (iv) 在小鼠、兔子、猫以及猴子中进行的单剂量和/或多剂量毒性研究； (v) 小鼠和兔子的粘膜、生殖和发育毒性研究； (vi) 使用人和酵母细胞进行细胞毒性、致突变性和基因毒性测试； (vii) 小鼠长期致癌性研究。在第一阶段提案中，我们测试了：(i) WHI-07 作为 HIV 性传播模型在家猫中预防 FIV 经阴道和经直肠传播的能力； (ii) 确定 WHI-07 在兔子模型中不存在发育毒性。我们发现，WHI-07 单独使用或与双（环戊二烯基）钒 (IV) 复合物二硫代氨基甲酸钒 (VDDTC) 组合使用，可通过生殖器暴露于粘膜传播的 FIV 感染的猫 T 细胞，有效保护家猫免受系统性 FIV 感染。为性活跃女性开发双功能抗艾滋病毒杀菌剂的临床潜力。在第二阶段资助下，我们建议测试 WHI-07 加 VDDTC 凝胶微乳的体内抗逆转录病毒和避孕功效以及安全性研究，以进一步探索 WHI-07 单独或与 VDDTC 组合作为阴道杀精剂的效用临床环境中的抗 HIV 杀菌剂。我们假设，与单独使用 WHI-07 相比，这两种具有不同作用机制的活性剂的组合将有可能提高双重保护的功效和持续时间，同时保持足够的安全性。 II 期研究的目标是 (i) 检验 WHI-07 加 VDDTC 凝胶微乳剂与单独使用 WHI-07 的最佳杀菌活性，以防止家猫因经阴道和经直肠感染 FIV 感染细胞而发生全身性 FIV 感染； (ii) 评估 WHI-07 加 VDDTC 凝胶微乳对兔子的体内避孕功效； (iii) 评估 WHI-07 加 VDDTC 凝胶微乳剂在兔子体内的粘膜安全性和发育毒性； (iv) 评估 WHI-07 加 VDDTC 凝胶微乳液的稳定性。拟议的第二阶段工作将补充和加强 Paradigm Pharmaceuticals 安全有效的双功能杀菌剂的发现和临床前开发，这可能为预防艾滋病毒性传播同时为妇女提供有效生育控制的新策略奠定基础。